State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Theranostics. 2021 Jan 1;11(6):2612-2633. doi: 10.7150/thno.52199. eCollection 2021.
Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by lung and liver metastatic models. The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.
转移是结直肠癌（CRC）高死亡率的主要原因。然而，CRC 转移的分子机制仍不清楚。在这里，我们报告了同源盒 B5（HOXB5）在促进 CRC 转移中的新作用，HOXB5 是同源盒家族的成员。免疫组织化学检测了 HOXB5 及其靶基因在人 CRC 中的表达。进行了染色质免疫沉淀和荧光素酶报告基因检测，以测量 HOXB5 对靶基因的转录调节。通过肺和肝转移模型评估 CRC 细胞的转移能力。HOXB5 的表达升高与 CRC 患者的远处转移、更高的 AJCC 分期和不良预后呈正相关。HOXB5 表达是 CRC 患者复发和生存的独立且显著的危险因素。HOXB5 的过表达通过反式激活转移相关基因 C-X-C 基序趋化因子受体 4（CXCR4）和整合素亚基β 3（ITGB3）促进 CRC 转移。CXCR4 的配体 C-X-C 基序趋化因子配体 12（CXCL12）通过细胞外调节蛋白激酶（ERK）/ETS 原癌基因 1、转录因子（ETS1）通路上调 HOXB5 的表达。HOXB5 的敲低降低了 CXCL12 增强的 CRC 转移。此外，CXCR4 的特异性抑制剂 AMD3100 显著抑制了 HOXB5 介导的 CRC 转移。HOXB5 表达与人 CRC 组织中 CXCR4 和 ITGB3 的表达呈正相关，并且 HOXB5/CXCR4 或 HOXB5/ITGB3 共表达阳性的患者预后最差。我们的研究表明 HOXB5 是 CRC 的预后生物标志物，并定义了 CXCL12-HOXB5-CXCR4 正反馈环，该环在促进 CRC 转移中起重要作用。
